Atherosclerosis is a multifactorial disease characterized by excessive intracellular lipid deposition in macrophages, leading to the formation of foam cells. The accumulation of lipid-loaded foam cells in the subendothelial space leads to formation of fatty streaks, which are the early atherosclerotic lesions. Oxidative modifications of lipids, specifically low-density lipoprotein, has been implicated as a major process in foam-cell formation.
Lipoxygenases are nonheme iron-containing enzymes that catalyze the oxygenation of certain polyunsaturated fatty acids such as lipoproteins. Several different lipoxygenase enzymes are known, each having a characteristic oxidation action. One specific lipoxygenase, namely 15-lipoxygenase (15-LO), has been detected in atherosclerotic lesions in mammals, specifically rabbit and man. The enzyme, in addition to its role in oxidative modification of lipoproteins, is important in the inflammatory reaction in the atherosclerotic lesion. Indeed, 15-LO has been shown to be induced in human monocytes by the cytokine IL-4, which is known to be implicated in the inflammatory process.
Inhibitors of 15-LO are especially useful to prevent and treat inflammatory diseases such as asthma, psoriasis, arthritis, and atherosclerosis. While there are several lipoxygenase enzymes, specific inhibition of 15-LO is important in the inflammatory and atherosclerosis process. A characteristic feature of atherosclerosis is the accumulation of cholesterol ester engorged foam cells. Foam cells are derived from circulating monocytes that invade artery walls in response to hypercholesterolemia, and mature into tissue macrophages. The enzyme 15-LO has been implicated in inflammatory disorders and in the origin and recruitment of foam cells (See Harats, et al., Trends Cardiovasc. Med., 1995;5(1):29-36). This enzyme is capable of oxidizing esterified polyenoic fatty acids, such as those found in phospholipids. Treatment of experimental animals with antioxidants which reduced hydroperoxides produced by 15-LO has been shown to retard the progression of atherosclerotic lesions. For example, Sendobry, et al., British Journal of Pharmacology, 1997;120:1199-1206 show suppression of atherogenesis in rabbits fed a high-fat diet and treated with a 15-LO inhibitor.